Enabling immunotherapy for high-risk Group 3 medulloblastoma via systems immunology

通过系统免疫学对高危 3 组髓母细胞瘤进行免疫治疗

基本信息

批准号：
10714138
负责人：
Hongbo Chi
金额：
$ 81.9万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-07 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10714138
关键词：
Address Adoptive Cell Transfers Atlases Biology Brain Neoplasms CAR T cell therapy CD8-Positive T-Lymphocytes CRISPR screen Cancer Etiology Cell Communication Cell Therapy Cell physiology Cells Cellular biology Child Childhood Malignant Brain Tumor Classification Clustered Regularly Interspaced Short Palindromic Repeats Data Development Disease Exclusion Exhibits Genetic Genetically Engineered Mouse Genomics Goals Heterogeneity Human Immune Immune Evasion Immunocompetent Immunology Immunotherapeutic agent Immunotherapy Joints Macrophage Maps Mediating Modeling Molecular Multiomic Data Mus Network-based PTPRC gene Patients Phenotype Pre-Clinical Model Proteomics Refractory Resistance Reverse engineering Saint Jude Children&apos s Research Hospital Sampling Signal Transduction Sorting Subgroup System Systems Biology T cell response T cell therapy T-Lymphocyte TCF Transcription Factor Technology Testing Tumor Immunity Tumor stage Tumor-infiltrating immune cells Visualization cancer type childhood cancer mortality chimeric antigen receptor T cells clinically relevant cloud based data visualization disorder risk experimental study functional genomics high risk high risk population improved in vivo insight medulloblastoma mouse model multiple omics neoplastic cell nerve stem cell notch protein novel overexpression screening single cell analysis single-cell RNA sequencing spatiotemporal stem-like cell tool transcriptomic profiling transcriptomics tumor tumor microenvironment tumor progression tumor-immune system interactions

项目摘要

PROJECT SUMMARY / ABSTRACT The goal of this project is to dissect the immune evasion mechanisms and enable immunotherapy for children with high-risk Group 3 medulloblastoma (G3MB) via systems immunology approaches. Brain tumors are the leading cause of cancer-related deaths in children. Medulloblastoma is the most prevalent malignant pediatric brain tumor and is characterized by four major molecular subgroups, among which G3MB is the most aggressive form and features MYC overexpression. The immunosuppressive tumor microenvironment (TME) is poorly understood in G3MB, and no immunotherapy is available for children with this high-risk disease. Systems immunology approaches—especially single-cell and spatial multi-omics profiling and in vivo CRISPR-based functional screening—have proven powerful in dissecting tumor–TME interactions and identifying novel immunotherapy targets in various cancer types, but very few studies have integrated these approaches. In our preliminary studies, we applied two unique immunocompetent genetically-engineered mouse models (GEMMs) of MYC-driven G3MB and performed scRNA-seq, scATAC-seq and spatial transcriptomics profiling. We enriched immune cells from the TME by sorting CD45 positive cells for single-cell studies. Our preliminary analysis of single-cell and spatial omics data revealed striking interactions of neural stem cell-like tumor cells with macrophages and other immune cells that potentially create a suppressive TME and drive immune evasion in mouse G3MB. We also performed in vivo CRISPR screening in tumor cells using the GEMMs to identify modulators of tumor development, which demonstrated the feasibility of in vivo functional genomics screening in our preclinical models. In this project, first, we propose to utilize cutting-edge single-cell and spatial omics technologies to characterize the two G3MB GEMMs at different stages of tumor progression. We will use our network-based tools to integrate these multi-omics data to dissect the dynamic tumor–immune interactions and underlying “hidden” drivers that drive the immune exclusion and suppression during G3MB progression. We will also validate discoveries of G3MB from mouse studies in patient samples. We will develop a cloud-based portal to visualize and explore our single-cell and spatial data and tumor–TME interactomes of G3MB. Second, we will establish the mechanistic basis of tumor–T cell interactions and strategies to enable adoptive T cell therapy for G3MB by discovering functional drivers and putative targets in both tumor cells and T cells. To this end, we will apply both candidate approach and in vivo CRISPR screening in immunocompetent GEMMs to identify tumor- intrinsic modulators that will remodel the suppressive TME and sensitize G3MB tumors to adoptive T cell and CAR-T cell therapies. We will also test if targeting inhibitory factors for T cell function will enable and optimize effective adoptive T cell therapies against such tumors. Our studies promise to provide new insights into mechanisms of tumor–TME interactions in G3MB and manifest legitimate immunotherapeutic opportunities.

项目摘要 /摘要该项目的目的是剖析免疫避免机制，并为儿童提供免疫疗法通过系统免疫学方法，具有高危组3髓母细胞瘤（G3MB）。脑肿瘤是儿童与癌症相关死亡的主要原因。髓母细胞瘤是最普遍的恶性儿科脑肿瘤，其特征是四个主要的分子亚组，其中G3MB是最具侵略性的形式和特征MYC的过表达。免疫抑制性肿瘤微环境（TME）较差在G3MB中了解齿，并且对于这种高风险疾病的儿童没有免疫疗法。系统免疫学方法 - 尤其是单细胞和空间多词分析以及基于Vivo CRISPR的功能性筛查 - 被证明在剖析肿瘤 - TME相互作用并识别新颖的方面被证明有力各种癌症类型的免疫疗法靶标，但很少有研究整合了这些方法。在我们的初步研究，我们应用了两个独特的免疫能力遗传工程小鼠模型（GEMM） MYC驱动的G3MB并进行了SCRNA-SEQ，SCATAC-SEQ和空间转录组学分析。我们丰富了通过对CD45阳性细胞排序单细胞研究，从TME中免疫细胞。我们对单细胞和空间上的OMIC数据揭示了神经干细胞样肿瘤细胞与巨噬细胞和其他可能产生抑制性TME并驱动免疫电池的免疫电池鼠标G3MB。我们还使用宝石在肿瘤细胞中进行了体内CRISPR筛查以识别肿瘤发育的调节剂，证明了体内功能基因组学筛查的可行性在我们的临床前模型中。在这个项目中，首先，我们建议利用尖端的单细胞和空间OMIC 在肿瘤进展的不同阶段表征两个G3MB GEMM的技术。我们将使用我们的基于网络的工具集成这些多摩管数据以剖析动态肿瘤 - 免疫相互作用和在G3MB进展过程中驱动免疫排除和抑制的基础“隐藏”驱动程序。我们将还从患者样品中的小鼠研究中验证了G3MB的发现。我们将开发基于云的门户可视化和探索我们的单细胞和空间数据以及G3MB的肿瘤– TME相互作用。第二，我们会的建立肿瘤– T细胞相互作用和策略的机械基础，以实现适应性T细胞治疗通过在肿瘤细胞和T细胞中发现功能驱动因素和推定靶标，G3MB。为此，我们将在免疫能力的宝石中同时应用候选方法和体内CRISPR筛查以鉴定肿瘤内在调节剂将重塑抑制性TME和敏感的G3MB肿瘤以适应性T细胞和 CAR-T细胞疗法。我们还将测试针对T细胞功能的抑制因素是否将启用和优化有效地针对此类肿瘤进行适应性T细胞疗法。我们的研究承诺将提供新的见解 G3MB中肿瘤与TME相互作用的机制和明显的合法免疫治疗机会。